This MDRU proposal is aimed at 1) testing novel pharmacotherapies for cocaine dependence, and 2) developing a systematic approach to implementing clinical trials for such testing. A substantial among of evidence has been collected indicating that dopamine mediates the actions of cocaine that are assumed to be related to its abuse liability. To date, targeting the dopamine systems has not been clinically fruitful, probably because of the complexity of cocaine's actions. We hypothesized that agents that module the dopamine system, such as the excitatory and inhibitory amino acids, may be more likely to be successful therapeutic agents for cocaine dependence. Theoretically, either increasing the inhibitory influence of GABA or decreasing the excitatory influence of the glutamate system on cocaine-induced increases in dopamine should reduce the reinforcing effects of cocaine. Therefore, we will test a series of glutamatergic antagonists and GABAergic agonists. To perturb the glutamate system, we will use memantine, a non-competitive NMDA antagonist GV-196771A, a glycine site antagonist; acamprosate, a partial agonist at the polyamine site; ACEA-1021, a glycine site antagonist; and LY-293558, an AMPA antagonist. To perturb the glutamate system, we will use a memantine, a non-competitive NMDA antagonist; GV- 196771A, a glycine site antagonist; and LY-293558, an AMPA antagonist. To perturb the GABA system, we will use gabapentin, a GABA analog; baclofen, a GABAB agonist; and abecarnil, a GABAA partial agonist. We are proposing a hierarchical series of clinical trials, studying medications at "late Phase II" (Project 1), "early Phase II" (Project 2), and "late Phase I" levels (Project 3). Project 1 will tet memantine and gabapentin, in sequential double-blind placebo-controlled trials (N=40/arm), each lasting 2.5 years. Project 2 will test GV 196771A and baclofen against placebo in a 3-arm double-blind placebo-controlled trial (N=20/arm), followed by a similar trial of acamprosate, abecarnil and placebo. Each trial will last 2.5 years. Project 3 will test, in successive years, in placebo-controlled double blind laboratory trials (N=20/study), acamprosate, abecarnil, ACEA 1021, and LY 293558. Projects 1 and 2 will begin in year 1, Project 3 will begin in year 2. This MDRU will have the capability to move among three models and compare data across them: 1) a placebo-controlled design in a classic trial; 2) an innovative outpatient 3-arm placebo-controlled design; and 3) the human laboratory. The believe this to be a rational and cost effective approach to testing potentially useful medications.